Design and Synthesis of Collybolide Probes for Kappa-Opioid Receptor

阿片κ受体胶内酯探针的设计与合成 摘要： 虽然μ-阿片类镇痛药如吗啡对严重疼痛有效，但由于 不必要的副作用，如呼吸抑制，身体依赖，心理成瘾，滥用 责任和瘙痒研究表明，选择性κ阿片受体（KOR）激动剂偏向于G- 蛋白质信号传导可能是治疗疼痛的新疗法，副作用减少。破译结构 通过新的化学探针对KOR选择性的必要要求是开发的第一步 选择性和偏置KOR配体。在寻找新的KOR化学探针的过程中，我们发现了一种名为collybolide的化合物， 从蘑菇Collybia maculata中提取的不含氮的倍半萜天然产物， 具有体内镇痛和抗过敏活性的选择性KOR激动剂。Collybolide具有呋喃基-δ-内酯核心 类似于鼠尾草素A，然而与后者的不同之处在于显示出沿着的50- 在阻断非组胺介导的瘙痒方面的效力高出一倍。这项研究计划的长期目标是 开发以KOR为基础的镇痛药和消炎药，减少副作用。本项目的目标是 开发用于鉴定具有所需的选择性和偏置性KOR配体的新的collybolide探针 用于体内的药理学特性。我们的假设是，合理的结构多样化的collybolide 将提供新的探针，以获得重要的结构信息，可能导致有效的发展， 用于治疗瘙痒和疼痛的治疗剂，其副作用减少。在强有力的初步数据的指导下， 这一假设将通过追求以下具体目标来检验：1）第一- 用于鉴定选择性和偏向性KOR配体的第二代collybolide探针; 2）设计、合成和表征 体内评价具有药物样性质的优化的Collybolide类似物以鉴定潜在的镇痛剂， 副作用减少的止痒剂。拟议的研究将由高素质的人员进行 在天然产物分离、有机合成和药用方面具有协同专长的研究人员团队 化学以及药理学、神经科学、计算对接和蛋白质结晶。的 本申请中的研究将全面地检查胶团内酯的结构-活性关系， 会产生一系列有选择性和偏见的具有成为先导药物潜力的OR配体 减少副作用的瘙痒和疼痛的候选人。此外，NIMH-PDSP的高通量筛选 针对50种CNS受体，可以找到新的命中，可以进一步优化，以探索新的治疗方法， 机会

Design and Synthesis of Collybolide Probes for Kappa-Opioid Receptor Abstract: While the mu-opiate analgesics such as morphine are effective for severe pain, their use is limited due to unwanted side effects such as respiratory depression, physical dependence, psychological addiction, abuse liability and itching. Studies suggest that selective kappa-opioid receptor (KOR) agonists biased towards G- protein signaling could be novel therapeutics to treat pain with reduced side effects. Deciphering the structural requirements essential for KOR selectivity through novel chemical probes is the first step in developing selective- and biased-KOR ligands. In the quest for new KOR chemical probes, we identified collybolide, a non-nitrogenous sesquiterpene natural product extracted from the mushroom Collybia maculata as a highly selective KOR agonist having in vivo analgesic and antipruritic activity. Collybolide has a furyl-δ-lactone core similar to that of salvinorin A, however differs from the latter in exhibiting functional selectivity along with a 50- fold higher potency in blocking non-histamine-mediated itch. The long-term goal of this research program is to develop KOR based analgesics and anti-pruritic drugs with reduced side effects. The objective of this project is the development of novel collybolide probes for identifying selective- and biased-KOR ligands with desirable pharmacological profiles for use in vivo. Our hypothesis is that rational structural diversification of collybolide will provide novel probes to gain important structural information that could lead to the development of effective therapeutics for the treatment of pruritus and pain with reduced side effects. Guided by strong preliminary data, this hypothesis will be tested by pursuing the following specific aims: 1) Synthesis and evaluation of first- generation collybolide probes for identifying selective-and biased KOR ligands; 2) Design, synthesis and in vivo evaluation of optimized collybolide analogues with drug-like properties to identify potential analgesics and anti-pruritus agents with reduced side-effects. The proposed research will be performed by a highly qualified team of researchers having synergistic expertise in natural products isolation, organic synthesis, and medicinal chemistry as well as in pharmacology, neuroscience, computational docking, and protein crystallization. The studies in this application will comprehensively examine the structure–activity relationships of collybolide and are expected to yield a set of selective- and biased-?OR ligands with the potential of becoming lead drug candidates for itch and pain with reduced side effects. Further, high-throughput screening at the NIMH-PDSP against 50 CNS receptors could find new hits, which could be optimized further to explore new therapeutic opportunities.